Granted Patent B2

US 12,577,240 · App. 18/004,996 · Granted Mar 17, 2026

Inventors: Dafydd Rhys Owen (Concord, MA); Martin Youngjin Pettersson (Littleton, MA); Matthew Richard Reese (Mystic, CT); Matthew Forrest Sammons (Quincy, MA); Jamison Bryce Tuttle (Marblehead, MA); Qingyi Yang (Lexington, MA)

Assignee: Pfizer Inc.

C07D417/14A61P31/14

Abstract

Claims (155)

1 . A compound of Formula I

or a pharmaceutically acceptable salt thereof;

wherein

A is S or O;

Z 1 , Z 2 , Z 3 and Z 4 are each independently CR 3 or N;

R 1 is selected from the group consisting of C 1 -C 6 alkyl, R 1b NH—C 1 -C 6 alkyl-, C 1 -C 6 alkoxy, (C 1 -C 6 alkoxy)-C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 3 -C 6 alkynyloxy, C 3 -C 12 cycloalkyl optionally fused with a 5- to 6-membered heteroaryl or phenyl, (C 3 -C 12 cycloalkyl)-C 1 -C 6 alkyl, C 3 -C 12 cycloalkoxy, (C 3 -C 12 cycloalkoxy)-C 1 -C 6 alkyl, 4- to 12-membered heterocycloalkyl which is optionally fused with a 5- to 6-membered heteroaryl or phenyl and wherein said heterocycloalkyl comprises one to four heteroatoms independently selected from N, O and S(O) n , (4- to 12-membered heterocycloalkyl)-C 1 -C 6 alkyl wherein said heterocycloalkyl moiety comprises one to four heteroatoms independently selected from N, O and S(O) n , C 6 -C 10 aryl optionally fused with a C 4 -C 6 cycloalkyl or a 4- to 7-membered heterocycloalkyl, (C 6 -C 10 aryl)-C 1 -C 6 alkyl, 5- to 10-membered heteroaryl comprising one to five heteroatoms independently selected from N, O and S, (5- to 10-membered heteroaryl)-C 1 -C 6 alkyl wherein the heteroaryl moiety comprises one to five heteroatoms independently selected from N, O and S, (5- to 10-membered heteroaryloxy)-C 1 -C 6 alkyl wherein the heteroaryl moiety comprises one to five heteroatoms independently selected from N, O and S, (5- to 6-membered heteroaryl)-(5- to 6-membered heteroaryl)- wherein each heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S, (4- to 7-membered heterocycloalkyl)-(5- to 6-membered heteroaryl)- wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O) n and the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S, and (5- to 6-membered heteroaryl)-(4- to 7-membered heterocycloalkyl)- wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O) n and the heteroaryl moiety comprises one to four heteroatoms independently selected from N, O and S; wherein each R 1 group is optionally substituted with one to five R 1a ;

R 1a at each occurrence is independently selected from the group consisting of oxo, halo, hydroxy, cyano, phenyl, amino, (C 1 -C 3 alkyl)amino, di(C 1 -C 3 alkyl)amino, C 1 -C 6 alkyl optionally substituted with one to five fluoro, C 1 -C 6 alkoxy optionally substituted with one to five fluoro, (C 1 -C 3 alkoxy)-C 1 -C 3 alkyl optionally substituted with one to five fluoro, C 3 -C 6 cycloalkyl optionally substituted with one to three substituents independently selected from fluoro and C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl-C 1 -C 6 alkyl, phenyl, phenyl-C 1 -C 6 alkyl, (C 1 -C 6 alkyl)-C(O)— and (C 1 -C 6 alkyl)-S(O) n —;

R 1b is selected from the group consisting of C 1 -C 6 alkyl-C(O)—, C 3 -C 6 cycloalkyl-C(O)—, C 1 -C 6 alkyl-OC(O)—, C 3 -C 6 cycloalkyl-OC(O)—, (C 1 -C 6 alkyl) 2 N—C(O)—, (C 1 -C 6 alkyl) 2 N—(C 1 -C 6 alkyl)-C(O)—, (C 1 -C 6 alkyl)-S(O) 2 —, (C 3 -C 6 cycloalkyl)-S(O) 2 —, (4- to 7-membered heterocycloalkyl)-OC(O)— wherein the heterocycloalkyl moiety comprises one to three heteroatoms independently selected from N, O and S(O) n , and 5- to 6-membered heteroaryl comprising one to three heteroatoms independently selected from N, O and S; wherein each R 1b group is optionally substituted with one to five fluoro or with one to two C 1 -C 3 alkyl;

R 2 at each occurrence is independently selected from the group consisting of fluoro, C 1 -C 6 alkyl optionally substituted with one to three fluoro, and C 1 -C 6 alkoxy optionally substituted with one to three fluoro; or two R 2 groups when attached to adjacent carbons and taken together with the carbons to which they are attached are a fused C 3 -C 6 cycloalkyl which is optionally substituted with one to four R 2a ; or two R 2 groups when attached to the same carbon and taken together with the carbon to which they are attached are a spiro C 3 -C 6 cycloalkyl which is optionally substituted with one to four R 2a ;

R 2a at each occurrence is independently selected from fluoro, C 1 -C 3 alkyl optionally substituted with one to five fluoro and C 1 -C 8 alkoxy optionally substituted with one to five fluoro;

R 3 at each occurrence is independently selected from hydrogen, halo, cyano, C 1 -C 6 alkyl optionally substituted with one to five fluoro, C 1 -C 6 alkoxy optionally substituted with one to five fluoro, and (C 1 -C 6 alkyl)-SO 2 —;

m is 1 or 2;

n at each occurrence is independently selected from 0, 1 and 2; and

p is 0, 1, 2, 3 or 4.

2 . The compound of claim 1 wherein

R 2 at each occurrence is independently selected from the group consisting of fluoro, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl and tert-butoxy; or two R 2 groups when attached to adjacent carbons and taken together with the carbons to which they are attached are a fused cyclohexane, cyclopentane or cyclopropane ring which is optionally substituted with one to four R 2a ; or two R 2 groups when attached to the same carbon and taken together with the carbon to which they are attached are a spirocyclopropane, spirocyclobutane, spirocyclopentane or spirocyclohexane ring which is optionally substituted with one to four R 2a ;

or a pharmaceutically acceptable salt thereof.

3 . The compound of claim 2 wherein R 2 ª at each occurrence is independently selected from the group consisting of fluoro, methyl, trifluoromethyl and methoxy;

or a pharmaceutically acceptable salt thereof.

4 . The compound of claim 1 wherein m is 1 and the moiety

is selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

5 . The compound of claim 1 wherein m is 2 and the moiety

is selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

6 . The compound of claim 1 wherein the moiety

is selected from the group consisting of

 and

R 3 is selected from the group consisting of halo, cyano, C 1 -C 6 alkyl optionally substituted with one to five fluoro, C 1 -C 6 alkoxy optionally substituted with one to five fluoro, and (C 1 -C 6 alkyl)-SO 2 —;

or a pharmaceutically acceptable salt thereof.

7 . The compound of claim 6 wherein R 3 is selected from the group consisting of chloro, cyano, methyl, trifluoromethyl, tert-butyl, methoxy and methylsulfonyl;

or a pharmaceutically acceptable salt thereof.

8 . The compound of claim 1 wherein R 1 is a 4- to 12-membered heterocycloalkyl which is optionally fused with a 5- to 6-membered heteroaryl or phenyl and wherein said heterocycloalkyl comprises one to four heteroatoms independently selected from N, O and S(O) n , or is a (4- to 12-membered heterocycloalkyl)-C 1 -C 6 alkyl wherein said heterocycloalkyl moiety comprises one to four heteroatoms independently selected from N, O and S(O) n ; each of which is optionally substituted with one to five R 1a , or a pharmaceutically acceptable salt thereof.

9 . The compound of claim 8 wherein the 4- to 12-membered heterocycloalkyl moiety in R 1 is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, pyranyl, 2-oxo-1,3-oxazolidinyl, oxabicyclo[2.2.1]heptyl, 1-oxa-8-azaspiro[4.5]decyl, 1,1-dioxido-1,2-thiazolidinyl and 1,1-dioxido-1,2-thiazinanyl; each of which is optionally substituted with one to three R 1a ; or a pharmaceutically acceptable salt thereof.

10 . The compound of claim 9 wherein R 1 is a 4- to 12-membered heterocycloalkyl selected from

or a pharmaceutically acceptable salt thereof.

11 . The compound of claim 1 wherein R 1 is selected from the group consisting of phenyl, a 5- to 10-membered heteroaryl comprising one to five heteroatoms independently selected from N, O and S; a (5- to 10-membered heteroaryl)-C 1 -C 6 alkyl wherein the heteroaryl moiety comprises one to five heteroatoms independently selected from N, O and S; and a (5- to 10-membered heteroaryloxy)-C 1 -C 6 alkyl wherein the heteroaryl moiety comprises one to five heteroatoms independently selected from N, O and S; each of which is optionally substituted with one to five R 1a ; or a pharmaceutically acceptable salt thereof.

12 . The compound of claim 11 wherein the 5- to 10-membered heteroaryl moiety in R 1 is selected from the group consisting of imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, quinolinyl, quinoxalinyl, benzotriazolyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b][1,3]thiazolyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,3]triazolo[1,5-a]pyridinyl and naphthyridinyl; each of which is optionally substituted with one to three R 1a ; provided that when R 1 is triazolyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl then R 1 is optionally substituted with one to two R 1a and when R 1 is oxadiazolyl then R 1 is optionally substituted with one R 1a ;

or a pharmaceutically acceptable salt thereof.

13 . The compound of claim 12 wherein R 1 is selected from the group consisting of indolyl, isoxazolyl, thiazolylmethyl, pyrazolyl, pyrazolylmethyl, triazolyl and triazolylmethyl; each of which is optionally substituted with one to three R 1a , provided that when R 1 is isoxazolyl, thiazolyl, triazolyl, thiazolylmethyl or triazolylmethyl then R 1 is optionally substituted with one to two R 1a ; or a pharmaceutically acceptable salt thereof.

14 . The compound of claim 1 wherein R 1 is R 1b NH—C 1 -C 6 alkyl-; or a pharmaceutically acceptable salt thereof.

15 . The compound of claim 14 wherein R 1b NH—C 1 -C 6 alkyl- is selected from

or a pharmaceutically acceptable salt thereof.

16 . The compound of claim 15 wherein R 1b is selected from the group consisting of CH 3 C(O)—, CF 3 C(O)—, CH 3 CH 2 C(O)—, (CH 3 ) 2 CHC(O)—, (CH 3 ) 3 CC(O)—, cyclopropyl-C(O)—, (3,3-difluorocyclobutyl)-C(O)—, (CH 3 ) 2 N—C(O)—, (CH 3 ) 2 N—CH 2 C(O)—, CH 3 OC(O)—, CH 3 CH 2 OC(O)—, (CH 3 ) 2 CHOC(O)—, (CH 3 ) 3 COC(O)—, (1-methylazetidin-3-yl)-OC(O)—, CH 3 S(O) 2 —, CH 3 CH 2 S(O) 2 —, (CH 3 ) 2 CHS(O) 2 —, (CH 3 ) 3 CS(O) 2 — and (cyclopropyl)-S(O) 2 —;

or a pharmaceutically acceptable salt thereof.

17 . The compound of claim 1 selected from the group consisting of

(6S)—N-{(2R)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-5-[(2R)-tetrahydrofuran-2-ylcarbonyl]-5-azaspiro[2.4]heptane-6-carboxamide;

N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-4,4-dimethyl-1-[(2R)-tetrahydrofuran-2-ylcarbonyl]-L-prolinamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-[(2R)-tetrahydrofuran-2-ylcarbonyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide;

tert-butyl (1R,2S,5S)-2-({(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-{[(2R)-5-oxotetrahydrofuran-2-yl]carbonyl}-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-{[(3R)-1-methyl-5-oxopyrrolidin-3-yl]carbonyl}-3-azabicyclo[3.1.0]hexane-2-carboxamide;

N-acetyl-L-valyl-N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-4,4-dimethyl-L-prolinamide;

N-(methoxycarbonyl)-L-valyl-N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-4,4-dimethyl-L-prolinamide;

(2S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-1-[N-(methylsulfonyl)-L-valyl]piperidine-2-carboxamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-{[(3R)-5-oxo-1-(propan-2-yl) pyrrolidin-3-yl]carbonyl}-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(1R,2S,5S)-3-(N-acetyl-3-methyl-L-valyl)-N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;

N-(cyclopropylcarbonyl)-L-valyl-N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-4,4-dimethyl-L-prolinamide;

(6S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-5-{(2S)-3-methyl-2-[(methylsulfonyl)amino]butanoyl}-5-azaspiro[2.4]heptane-6-carboxamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-3-{[(3R)-1-(cyclopropylmethyl)-5-oxopyrrolidin-3-yl]carbonyl}-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-3-{[(3R)-1-cyclobutyl-5-oxopyrrolidin-3-yl]carbonyl}-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(2S,4R)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-4-methyl-1-[N-(methylsulfonyl)-L-valyl]piperidine-2-carboxamide;

(2S,4S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-4-methyl-1-[N-(methylsulfonyl)-L-valyl]piperidine-2-carboxamide;

N-(methylsulfonyl)-L-valyl-N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-4,4-dimethyl-L-prolinamide;

(2S,4R)—N-{(2S)-1-(1,3-benzoxazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-4-methyl-1-[N-(trifluoroacetyl)-L-valyl]piperidine-2-carboxamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-3-{[(3R)-1-tert-butyl-5-oxopyrrolidin-3-yl]carbonyl}-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-(3-methyl-N-propanoyl-L-valyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-[N-(methylsulfonyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(1S,3aR,6aS)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-2-{(2S)-3-methyl-2-[(methylsulfonyl)amino]butanoyl}octahydro cyclopenta[c]pyrrole-1-carboxamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzoxazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-[N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(2S,4S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-4-ethyl-1-[N-(methylsulfonyl)-L-valyl]piperidine-2-carboxamide;

(2S,4R)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-4-ethyl-1-[N-(methylsulfonyl)-L-valyl]piperidine-2-carboxamide;

N-(methylsulfonyl)-L-valyl-(3R)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-3-propan-2-yl-L-prolinamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-3-[N-(cyclopropylcarbonyl)-3-methyl-L-valyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(2S,4R)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-4-methyl-1-[N-(trifluoroacetyl)-L-valyl]piperidine-2-carboxamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-[3-methyl-N-(2-methylpropanoyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(2S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-4-methyl-2-{7-[(methylsulfonyl)amino]-1-oxo-1,3-dihydro-2H-isoindol-2-yl}pentanamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-{[(3R)-5-oxo-1-phenylpyrrolidin-3-yl]carbonyl}-3-azabicyclo[3.1.0]hexane-2-carboxamide;

tert-butyl {(2S)-1-[(2S,4R)-2-({(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}carbamoyl)-4-methylpiperidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-[3-methyl-N-(methylsulfonyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-3-[N-(ethylsulfonyl)-L-valyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(3S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-2-{(2S)-3-methyl-2-[(methylsulfonyl)amino]butanoyl}-2-azaspiro[4.4]nonane-3-carboxamide;

(1S,3aR,7aS)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-2-{(2S)-3-methyl-2-[(methylsulfonyl)amino]butanoyl}octahydro-1H-isoindole-1-carboxamide;

(2S,4S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-1-[N-(methylsulfonyl)-L-valyl]-4-(propan-2-yl) piperidine-2-carboxamide;

(2S,4R)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-1-[N-(methylsulfonyl)-L-valyl]-4-(propan-2-yl) piperidine-2-carboxamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-[N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-{N-[(2S)-1, 1,1-trifluoropropan-2-yl]-L-valyl}-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-3-[N-(2,2-dimethylpropanoyl)-3-methyl-L-valyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-3-{[(3R)-1-benzyl-5-oxopyrrolidin-3-yl]carbonyl}-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-3-[N-(cyclopropylsulfonyl)-L-valyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-[N-(propan-2-ylsulfonyl)-D-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-[N-(propan-2-ylsulfonyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(2S,4S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-4-tert-butyl-1-[N-(methylsulfonyl)-L-valyl]piperidine-2-carboxamide;

(2S,4R)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-4-tert-butyl-1-[N-(methylsulfonyl)-L-valyl]piperidine-2-carboxamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide;

N-(methylsulfonyl)-L-valyl-(4R)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-4-tert-butoxy-L-prolinamide;

tert-butyl {(2S)-1-[(1R,2S,5S)-2-({(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hex-3-yl]-3,3-dimethyl-1-oxobutan-2-yl}carbamate;

(1R,2S,5S)—N-{(2S)-1-(4-chloro-1,3-benzoxazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-[N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(2S,4S)-4-methyl-1-[N-(methylsulfonyl)-L-valyl]-N-{(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1-[4-(trifluoromethyl)-1,3-benzoxazol-2-yl]propan-2-yl}piperidine-2-carboxamide;

(2S,4R)-4-methyl-1-[N-(methylsulfonyl)-L-valyl]-N-{(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1-[4-(trifluoromethyl)-1,3-benzoxazol-2-yl]propan-2-yl}piperidine-2-carboxamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-3-[N-(cyclopropylsulfonyl)-3-methyl-L-valyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-3-[N-(tert-butylsulfonyl)-L-valyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-[3-methyl-N-(propan-2-ylsulfonyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide;

methyl {(2S)-1-[(1R,2S,5S)-6,6-dimethyl-2-({(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1-[4-(trifluoromethyl)-1,3-benzoxazol-2-yl]propan-2-yl}carbamoyl)-3-azabicyclo[3.1.0]hex-3-yl]-3,3-dimethyl-1-oxobutan-2-yl}carbamate;

(2S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6-methyl-3-[N-(methylsulfonyl)-L-valyl]-6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(2S,4R)-4-methyl-1-[N-(methylsulfonyl)-L-valyl]-N-{(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1-[4-(trifluoromethyl)-1,3-benzothiazol-2-yl]propan-2-yl}piperidine-2-carboxamide;

(2S,4S)-4-methyl-1-[N-(methylsulfonyl)-L-valyl]-N-{(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1-[4-(trifluoromethyl)-1,3-benzothiazol-2-yl]propan-2-yl}piperidine-2-carboxamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-3-[N-(tert-butylsulfonyl)-3-methyl-L-valyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(2S,4R)-4-methyl-N-{(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1-[4-(trifluoromethyl)-1,3-benzoxazol-2-yl]propan-2-yl}-1-[N-(trifluoroacetyl)-L-valyl]piperidine-2-carboxamide;

ethyl {(2S)-1-[(1R,2S,5S)-6,6-dimethyl-2-({(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1-[4-(trifluoromethyl)-1,3-benzoxazol-2-yl]propan-2-yl}carbamoyl)-3-azabicyclo[3.1.0]hex-3-yl]-3,3-dimethyl-1-oxobutan-2-yl}carbamate;

(1R,2S,5S)-6,6-dimethyl-3-(3-methyl-N-propanoyl-L-valyl)-N-{(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1-[4-(trifluoromethyl)-1,3-benzothiazol-2-yl]propan-2-yl}-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(1R,2S,5S)-6,6-dimethyl-3-[N-(methylsulfonyl)-L-valyl]-N-{(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1-[4-(trifluoromethyl)-1,3-benzothiazol-2-yl]propan-2-yl}-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(1R,2S,5S)-6,6-dimethyl-3-[N-(methylsulfonyl)-L-valyl]-N-{(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1-[7-(trifluoromethyl)-1,3-benzothiazol-2-yl]propan-2-yl}-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(1R,2S,5S)-6,6-dimethyl-N-{(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1-[4-(trifluoromethyl)-1,3-benzoxazol-2-yl]propan-2-yl}-3-[N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(2S,4R)-4-methyl-N-{(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1-[4-(trifluoromethyl)-1,3-benzothiazol-2-yl]propan-2-yl}-1-[N-(trifluoroacetyl)-L-valyl]piperidine-2-carboxamide;

ethyl {(2S)-1-[(1R,2S,5S)-6,6-dimethyl-2-({(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1-[4-(trifluoromethyl)-1,3-benzothiazol-2-yl]propan-2-yl}carbamoyl)-3-azabicyclo[3.1.0]hex-3-yl]-3,3-dimethyl-1-oxobutan-2-yl}carbamate;

(1R,2S,5S)-6,6-dimethyl-3-[3-methyl-N-(methylsulfonyl)-L-valyl]-N-{(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1-[4-(trifluoromethyl)-1,3-benzothiazol-2-yl]propan-2-yl}-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(1R,2S,5S)-6,6-dimethyl-N-{(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1-[4-(trifluoromethyl)-1,3-benzothiazol-2-yl]propan-2-yl}-3-[N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-3-[N-(methylsulfonyl)-L-valyl]-6,6-bis(trifluoromethyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(1R,2S,5S)-6,6-dimethyl-3-[3-methyl-N-(methylsulfonyl)-L-valyl]-N-{(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1-[4-(trifluoromethyl)-1,3-benzoxazol-2-yl]propan-2-yl}-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(1R,2S,5S)-6,6-dimethyl-3-[N-(methylsulfonyl)-L-valyl]-N-{(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1-[4-(trifluoromethyl)-1,3-benzoxazol-2-yl]propan-2-yl}-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(1R,2S,5S)-6,6-dimethyl-N-{(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1-[4-(trifluoromethyl)-1,3-benzoxazol-2-yl]propan-2-yl}-3-[N-(propan-2-ylsulfonyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide; and

(1R,2S,5S)-6,6-dimethyl-3-[3-methyl-N-(propan-2-ylsulfonyl)-L-valyl]-N-{(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1-[4-(trifluoromethyl)-1,3-benzoxazol-2-yl]propan-2-yl}-3-azabicyclo[3.1.0]hexane-2-carboxamide;

or a pharmaceutically acceptable salt thereof.

18 . A compound of claim 1 selected from the group consisting of

(6S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-5-{(2S)-3-methyl-2-[(methylsulfonyl)amino]butanoyl}-5-azaspiro[2.4]heptane-6-carboxamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-3-[(4-methoxy-1H-indol-2-yl) carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-[N-(methylsulfonyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(1R,2S,5S)-6,6-dimethyl-3-[N-(methylsulfonyl)-L-valyl]-N-{(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1-[4-(trifluoromethyl)-1,3-benzothiazol-2-yl]propan-2-yl}-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-[N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide;

tert-butyl {(2S)-1-[(1R,2S,5S)-2-({(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-3,3-dimethyl-1-oxobutan-2-yl}carbamate;

(1R,2S,5S)-6,6-dimethyl-3-[N-(methylsulfonyl)-L-valyl]-N-{(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]-1-[7-(trifluoromethyl)-1,3-benzothiazol-2-yl]propan-2-yl}-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-[(2R)-tetrahydrofuran-2-ylcarbonyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(6S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-5-[(2R)-tetrahydrofuran-2-ylcarbonyl]-5-azaspiro[2.4]heptane-6-carboxamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-3-[N-(cyclopropylsulfonyl)-L-valyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-3-[N-(tert-butylsulfonyl)-3-methyl-L-valyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-3-[N-(tert-butylsulfonyl)-L-valyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-[3-methyl-N-(2-methylpropanoyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-(3-methyl-/-propanoyl-L-valyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-3-[N-(ethylsulfonyl)-L-valyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-3-[N-(2,2-dimethylpropanoyl)-3-methyl-L-valyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(1R,2S,5S)—N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-[3-methyl-N-(methylsulfonyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide;

(1R,2S,5S)-3-(N-acetyl-3-methyl-L-valyl)-N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; and

N-{(2S)-1-(1,3-benzothiazol-2-yl)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-4,4-dimethyl-1-[(2R)-tetrahydrofuran-2-ylcarbonyl]-L-prolinamide;

or a pharmaceutically acceptable salt thereof.

19 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

20 . A method of treating COVID-19 in a patient, the method comprising administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof to a patient in need thereof; wherein treating COVID-19 does not include preventing COVID-19.

21 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 14 or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

22 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 17 or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

23 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 18 or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

24 . A method of treating a coronavirus infection in a patient, the method comprising administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof to a patient in need thereof; wherein treating a coronavirus infection does not include preventing a coronavirus infection.

25 . A method of treating a coronavirus infection in a patient, the method comprising administering a therapeutically effective amount of a compound of claim 14 or a pharmaceutically acceptable salt thereof to a patient in need thereof; wherein treating a coronavirus infection does not include preventing a coronavirus infection.

26 . A method of treating a coronavirus infection in a patient, the method comprising administering a therapeutically effective amount of a compound of claim 17 or a pharmaceutically acceptable salt thereof to a patient in need thereof; wherein treating a coronavirus infection does not include preventing a coronavirus infection.

27 . A method of treating a coronavirus infection in a patient, the method comprising administering a therapeutically effective amount of a compound of claim 18 or a pharmaceutically acceptable salt thereof to a patient in need thereof; wherein treating a coronavirus infection does not include preventing a coronavirus infection.

Assignments (1)

Continuity (2)

References Cited (400)